US5723125A - Hybrid with interferon-alpha and an immunoglobulin Fc linked through a non-immunogenic peptide - Google Patents
Hybrid with interferon-alpha and an immunoglobulin Fc linked through a non-immunogenic peptide Download PDFInfo
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- US5723125A US5723125A US08/719,331 US71933196A US5723125A US 5723125 A US5723125 A US 5723125A US 71933196 A US71933196 A US 71933196A US 5723125 A US5723125 A US 5723125A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/555—Interferons [IFN]
- C07K14/56—IFN-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Definitions
- Interferon- ⁇ was among the first of the cytokines to be produced by recombinant DNA technology and has been shown to have therapeutic value in conditions such as inflammatory, viral, and malignant diseases.
- IFN ⁇ preparations including those purified from the natural sources and those generated by recombinant DNA technology, have been used or are being tested in a variety of malignant and viral diseases. IFN ⁇ can cause regression of some established tumors and induce positive responses in some viral infections.
- IFN ⁇ has been approved or tested in many countries for indications such as: Kaposi's sarcoma; hairy cell leukemia; malignant melanoma; basal cell carcinoma; multiple myeloma; renal cell carcinoma, hepatitis B; hepatitis C; venereal warts, Herpes I/II, varicella/herpes zoster; and mycosis fungoides.
- cytokines including IFN ⁇
- IFN ⁇ have relatively short circulation half-lives since they are produced in vivo to act locally and transiently.
- the serum half-life of IFN ⁇ is only about two to eight hours (Roche Labs. Referon A, Schering Intron A, Physicians' Desk Reference, 47th edition, 1993, pp. 2006-2008, 2194-2201).
- one of the recommended therapeutic strategies for the AIDS-related Kaposi's sarcoma starts with an induction dose of 36 million IU daily for 10 to 12 weeks, administered as an intramuscular or subcutaneous injection, followed by a maintenance dose of 36 million IU, three times a week. (Roche Labs.
- Immunoglobulins of IgG and IgM class are among the most abundant proteins in the human blood. They circulate with half-lives ranging from several days to 21 days. IgG has been found to increase the half-lives of several ligand binding proteins (receptors) when used to form recombinant hybrids, including the soluble CD4 molecule, LHR, and IFN-y receptor (Mordenti J. et al., Nature, 337:525-31, 1989; Capon, D. J. and Lasky, L. A., U.S. Pat. No. 5,116,964; Kurschner, C. et al., J. Immunol. 149:4096-4100, 1992).
- ligand binding proteins receptors
- hybrids can present problems in that the peptide at the C-terminal of the active moeity and the peptide at the N-terminal of the Fc portion at the fusion point creates a new peptide sequence, which is a neoantigen, and which can be immunogenic.
- the invention relates to a IFN ⁇ -Fc hybrid which is designed to overcome this problem and extend the half-life of the IFN ⁇ .
- the present invention relates to a hybrid recombinant protein which consists of two subunits.
- Each subunit includes a human interferon, preferably IFN ⁇ , joined by a peptide linker which is primarily composed of a T cell inert sequence, linked to a human immunoglobulin Fc fragment, preferably the ⁇ 4 chain.
- the ⁇ 4 chain is preferred over the ⁇ 1 chain because the former has little or no complement activating ability.
- the C-terminal end of the IFN ⁇ is linked to the N-terminal end of the Fc fragment.
- An additional IFN ⁇ (or other cytokine) can attach to the N-terminal end of any other unbound Fc chains in the Fc fragment, resulting in a homodimer for the ⁇ 4 chain. If the Fc fragment selected is another chain, such as the ⁇ chain, then, because the Fc fragments form pentamers with ten possible binding sites, this results in a molecule with interferon or other cytokine linked at each of ten binding sites.
- the two moieties of the hybrid are linked through a T cell immunologically inert peptide (e.g., Gly Gly Ser Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser (SEQ ID NO:1)).
- This peptide itself is immunologically inactive.
- the insertion of this peptide at the fusion point eliminates the neoantigenicity created by the joining of the two peptide moeities.
- the linker peptide also increases the flexibility of these moieties and allows retention of the biological activity. This relatively long linker peptide helps overcome the possible steric hindrance from the Fc portion of the hybrid, which could interfere with the activity of the hybrid.
- the hybrid has a much longer half-life than the native IFN ⁇ . Due to the linker, it is also designed to reduce the possibility of generating a new immunogenic epitope (a neoantigen) at what would otherwise be the fusion point of the IFN ⁇ and the immunoglobulin Fc segment.
- Cytokines are generally small proteins with relatively short half-lives which dissipate rapidly among various tissues, including at undesired sites. It is believed that small quantities of some cytokines can cross the blood-brain barrier and enter the central nervous system, thereby causing severe neurological toxicity.
- the IFN ⁇ linked to Fcy of the present invention would be especially suitable for treating hepatitis B or C, because these products will have a long retention time in the vasculature (upon intravenous adminstration) and will not penetrate undesired sites.
- the specific hybrid described can also serve as a model for the design and construction of other cytokine-Fc hybrids.
- the same or a similar linker could be used in order to reduce the possibility of generating a new immunogenic epitope while allowing retention of the biological activity.
- Cytokine-Fc hybrids in which interleukin-2 is the cytokine, or hybrids including other cytokines, could be made using the same techniques.
- the hybrid molecule of the invention includes an interferon moiety linked through a unique linker to an immunoglobulin Fc moiety.
- the C-terminal ends of two interferon moieties are separately attached to each of the two N-terminal ends of a heavy chain ⁇ 4 Fc fragment, resulting in a homodimer structure.
- a unique linker peptide, Gly Gly Ser Gly Gly Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Gly Ser (SEQ ID NO:1) was created to link the two moieties.
- the complete nucleotide sequence of the preferred ⁇ 4 hybrid appears in SEQ ID NO: 7.
- the linker is located at amino acid residue numbers 189 to 204.
- the advantage of the hybrid over the native cytokine is that the half-life in vivo is much longer.
- the hybrid including interferon and the ⁇ 4 chain Fc homodimer is larger than the native interferon. Because the pores in the blood vessels of the liver are large, this larger molecule is more suitable for use in treating hepatitis, where the virus responsible primarily affects the liver.
- the linker peptide is designed to increase the flexibility of the two moieties and thus maintain their biological activity.
- the interferon and the immunoglobulin are both of human origin, there is always a possibility of generating a new immunogenic epitope at the fusion point of the two molecules. Therefore, the other advantage of the linker of the invention, which consists mainly of a T cell inert sequence, is to reduce immunogenicity at the fusion point. Referring to SEQ ID NO:7, it can be seen that if the linker (residue numbers 189-204) was not present, a new sequence consisting of the residues immediately before number 189 and immediately after 204 would be created. This new sequence would be a neoantigen for the human body.
- Human IFN ⁇ is derived from a family of several different genes. More than 24 species have been identified so far, from gene and protein sequence data. They differ from each other by anywhere from a few to a maximum of 35 amino acids. Most of the species have a signal peptide sequence of 23 amino acid residues and a mature amino acid sequence of 166 amino acid residues (Goeddel, D. V. et al., Nature, 290:20-26, 1981; Weissmann, C. and Weber, H., Prog. Nuc. Acid Res. Mol. Biol. 33:251-300, 1986; Zoon, K. C., Interferon, 9:1-12, 1987).
- IFN ⁇ 2 (also called IFN ⁇ A) is one of the most intensively studied interferon species.
- the recombinant version of IFN ⁇ 2 has been used as a therapeutic for several years.
- Two IFN ⁇ 2 recombinant products, IFN ⁇ 2a and IFN ⁇ 2b, are now commercially available. They differ only in one amino acid at position 23, and there is no significant difference in biological activity between them (von Gabain, A., et al., Eur. J. Biochem. 190:257-61, 1990).
- IFN ⁇ 2a was selected as the fusion partner for the interferon hybrid of the invention, although the IFN ⁇ 2b or any other interferon species (including IFN ⁇ ) can be used as well. It is also possible to make similar constructs with other cytokines, such as interleukin-1 or interleukin-2. The same linker could be used, or another one which is not immunogenic and which maintains the biological activity of the contruct could be substituted.
- the advantages of the ⁇ 4 chain as the Fc moiety in the hybrid is that it is stable in the human circulation.
- the ⁇ 4 chain (unlike the ⁇ 1 chain) also avoids the wide spectrum of secondary biological properties, such as complement fixation and antibody-dependant cell-mediated cytotoxicity (ADCC), which may be undesirable properties.
- ADCC antibody-dependant cell-mediated cytotoxicity
- the cDNA of the IFN ⁇ 2a can be obtained by reverse transcription and PCR, using RNA extracted from leukocytes which express IFN ⁇ .
- RNA extracted from leukocytes which express IFN ⁇ can be obtained from the American Type Culture Collection (ATCC) in Rockville, Md., where it is held under number CCL 246.
- ATCC American Type Culture Collection
- the cells were challenged by Sendai virus to increase their transcription of interferons (Cantell, K. et al., Methods in Enzymology, 78A:29-38, Adacemic Press, 1981).
- IFN ⁇ is a collection of IFN species and each cell expresses several different IFN ⁇ subspecies at the same time.
- the DNA sequence homology among these species is so high that RT-PCR would probably amplify a group of them instead a specific one.
- the PCR primers were designed so that the last nucleotides of the two primers ended at positions where the amino acids coded are unique for IFN ⁇ 2a. These are position S22 and 161, respectively (See Zoon, K. C. Interferon, 9:1-12, 1987).
- the two gene segments from PCR can be separately cloned into cloning vectors. This makes the DNA sequencing easier and quicker since both segments are only a few hundred base pairs in length. Once the clones with the correct DNA sequences are identified, the two gene segments can be linked together through the BamH I site. No second round overlapping PCR and subsequent DNA sequencing of the full length segment are required.
- the yeast expression system Pichia Pastoris overcomes some of the problems encountered when using the bacterial system. It usually gives a high yield and has the ability to do various post-translational modifications. The expressed foreign protein can be secreted into the culture supernatant where not many other proteins reside, making protein purification and process scale-up much easier.
- This system was tried first to express either the IFN ⁇ -Fc hybrid or the wild type IFN ⁇ 2a. Unfortunately the IFN ⁇ -Fc secreted was found to be partially degraded on SDS-PAGE, whereas the IFN ⁇ 2a alone was not. The degradation was believed to be caused by the protease activities present in the yeast expression system, as reported by Scorer, C. A. et al., Gene, 136:111-9, 1993. The relatively weak spot in the hinge region is the possible target for the proteases.
- a mammalian cell expression system for the IFN ⁇ -Fc hybrid was also tried.
- the cells were selected by G418 at a concentration of 0.8 mg/ml.
- the IFN ⁇ -Fc expressing clones were identified by ELISA.
- the hybrid was successfully expressed in this system and there was no degradation.
- the recombinant protein is secreted into the culture supernatant and there is no aggregation, thereby simplifying purification.
- One chromatography step using a protein A column yields a purified IFN ⁇ -Fc protein.
- the protein produced in this system has a glycosylation pattern very similar to the natural molecules since it is expressed by mammalian cells.
- a native IFN ⁇ 2a signal peptide sequence is included in the expression vector. Therefore the protein secreted from the cells has an authentic N-terminal, whereas in the E. coli or yeast expression systems there either is no signal peptide or a non-IFN ⁇ signal peptide is used. Either way, it will bring in additional artificial amino acid residue(s) at the N-terminal end of the recombinant IFN ⁇ -Fc.
- the purification of the IFN ⁇ -Fc recombinant protein from the culture supernatant is relatively straightforward.
- the protein with a purity of more than 90%, as judged by SDS-PAGE, can be easily obtained by one step of affinity chromatography with a protein A column.
- the hybrid of SEQ ID NO:7 is expected to have a longer half-life in vivo than native IFN ⁇ , even though its specific activity is lower, this novel hybrid is expected to be preferred to the native IFN ⁇ for clinical use. This is because, as a result of the longer half-life, the Cxt (the area under the concentration vs. time curve) would be up to several hundred times greater than for the native IFN ⁇ . This means that at the equivalent molar dosage of the native IFN ⁇ and the hybrid, the latter would provide a several hundred fold increased exposure to IFN ⁇ , resulting in vastly increased efficacy at the same dosage, and less frequent administration.
- molar dosage is preferred instead of expressing activity as units per mass of protein. This is because interferons function through the binding to their specific receptors, which is directly related to the number of molecules present. Also, the molecular weight of the IFN ⁇ -Fcy4, 110 Kd, is more than five-fold larger than that of the wild type IFN ⁇ 2a, which is 20 kd. Taking this into consideration, measuring activity in units/ ⁇ mol instead of the units/mg provides a better comparison of activity specifity.
- Example 1 Cloning human IFN ⁇ cDNA and constructing the IFN ⁇ -Fc expression vector
- RNA-ZOL RNA isolation kit BIOTEX, Houston, Tex.
- the first-strand cDNA was synthesized by reverse transcription using AMV reverse transcriptase with oligo(dT) as 3' primer in 50 mM Tris-HCl (pH 8.3), 60 mMKCl, and 6 mM MgCl 2 , incubated at 42° C. for 1 hour.
- the reaction mixture was used directly as the template for PCR to amplify IFN ⁇ cDNA.
- the 5' primer for PCR contained a Hind III site and the coding sequence for the first 21 amino acids from the IFN ⁇ 2a leader peptide (SEQ ID NO:3).
- the 3' primer contained the sequence coding for part of the linker (SEQ ID NO:1) and the last five amino acids of the IFN ⁇ 2a, and a BamH I site integrated in the linker sequence (SEQ ID NO:4).
- the PCR buffer contained 50 mM KCl, 10 mMTris-Hcl (pH8.3), 1.5 mM MgCl 2 , 0.01% gelatin, 0.1 mmol each of dNTP, 0.5 ⁇ mol of each primers, 5 ⁇ l RT reaction mixture, and 1 unit of Taq DNA polymerase in a total of 50 ⁇ l volume.
- the PCR condition was 94° C. (1 min), 55° C. (2 min), and 72° C. (2 min) for 40 cycles on a GeneAmp PCR System 9600 (Perkin Elmer, Norwalk, Conn.).
- the cDNA of the human immunoglobulin ⁇ 4 Fc was obtained by reverse transcription and PCR performed the same way as described above.
- the RNA was extracted from the human tonsil B cells.
- the 5' primer had the sequence shown in SEQ ID NO:5.
- the 3' primer had the sequence shown in SEQ ID NO: 6.
- the two PCR amplified DNA segments were cloned into pUC18 vectors at sites Hind III/BamH I or sites BamH I/EcoR I respectively. After their DNA sequences were confirmed by DNA sequencing using the kit from USB (Cleveland, Ohio), the two segments were ligated together through the BamH I site by a second round cloning. The full length IFN ⁇ -Fc cDNA was then inserted into a mammalian expression vector pCDNA3 (Invitrogen, San Diego, Calif.) through the Hind III and EcoR I sites.
- Colonies appeared in one week and they were ready for screening in two weeks.
- the supernatants from each well with a single colony growing were collected.
- the IFN ⁇ -Fc in the supernatant was quantitatively determined by an ELISA assay employing goat anti-human IgG and anti-human Fc conjugated with horseradish peroxidase.
- the clones with higher ELISA readings and smaller colony size were selected for subcloning. These colonies were transferred to a 24-well plate and supplied with a medium containing G418.
- the clone with the highest secretion level was expanded and adapted to grow in a spinner.
- the culture supernatant was collected and passed through a protein A agarose column equilibrized by PBS.
- the protein bound to the protein A was eluted by 50 mM citric acid (pH 3.0) and concentrated by lyophilization.
- the purity of the recombinant protein isolated from NSO culture medium was examined by SDS-PAGE and Western blot. Only one protein band was visible on the blotted membrane stained by ponceau s for total proteins, showing a homogeneity of the protein preparation.
- the apparent molecular weight of this protein is about 55 kd under reducing conditions and 110 kd under non-reducing conditions, which is exactly the predicted size for the IFN ⁇ -Fc hybrid. The doubling of its apparent molecular weight under non-reducing conditions suggests that the hybrid is in a dimeric form.
- the recombinant protein can be recognized by both anti-Fc and anti-IFN ⁇ antibodies, confirming that it consists of two moieties, the IFN ⁇ and the Fc fragment.
- the bioactivity assay for the IFN ⁇ -Fc was an antiviral assay.
- the assay method used was a modification of the protocol described by Robert M. Friedman et al (Measurement of antiviral activity induced by interferons ⁇ , ⁇ , and y, Current Protocols in Immunology, 1994, pp. 6.9.1-6.9.8). Briefly, human lung carcinoma cells (A549, ATCC#CCL 185) were seeded in 96-well plates at a density of 40,000 cells/well and incubated at 37° C. for 24 hours. 1:2 serial diluted IFN ⁇ -Fc hybrid or native IFN ⁇ (NIH# Gxa01-901-535) were added and incubated at 37° C. for 24 hours.
- the culture medium was replaced with a fresh one containing encephalomyocarditis virus (ATCC #VR 129B) at a concentration of about 0.1 MOI/cell and incubated at 37° C. for a further 48 hours.
- the dead cells were washed away by pipetting up and down vigorously with PBS.
- the attached cells were fixed by 2% formaldehyde and stained by giemsa stain.
- the plates were rinsed with tap water and allowed to dry.
- the stained cells were dissolved by methanol and the samples were read spectrophotometrically at 595 nm.
- the antiviral activity of IFN ⁇ -Fc hybrid was calculated by comparing it with the IFN ⁇ standard, and was found to be about 30 to 60% of the activity of the IFN ⁇ standard.
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Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/719,331 US5723125A (en) | 1995-12-28 | 1996-09-25 | Hybrid with interferon-alpha and an immunoglobulin Fc linked through a non-immunogenic peptide |
MYPI96005143A MY116588A (en) | 1995-12-28 | 1996-12-06 | Hybrid with interferon-(alpha) and an immunoglobulin fc linked through a non-immunogenic peptide |
EP96945126A EP0888122B1 (de) | 1995-12-28 | 1996-12-13 | HYBRID AUS INTERFERON-alpha UND IMMUNGLOBULIN Fc-FRAGMENT VERBUNDEN DURCH EIN NICHT IMMUNOGENES PEPTID |
DE69636938T DE69636938T2 (de) | 1995-12-28 | 1996-12-13 | HYBRID AUS INTERFERON-alpha UND IMMUNGLOBULIN Fc-FRAGMENT VERBUNDEN DURCH EIN NICHT IMMUNOGENES PEPTID |
CNB961994223A CN1187086C (zh) | 1995-12-28 | 1996-12-13 | 具有经非免疫原性肽连接在一起的干扰素α和免疫球蛋白Fc的杂合体 |
AT96945126T ATE355074T1 (de) | 1995-12-28 | 1996-12-13 | Hybrid aus interferon-alpha und immunglobulin fc- fragment verbunden durch ein nicht immunogenes peptid |
CA002239522A CA2239522A1 (en) | 1995-12-28 | 1996-12-13 | Hybrid with interferon-.alpha. and an immunoglobulin fc linked through a non-immunogenic peptide |
AU13567/97A AU701579B2 (en) | 1995-12-28 | 1996-12-13 | Hybrid with interferon-alpha and an immunoglobulin Fc linked through a non-immunogenic peptide |
PCT/US1996/020861 WO1997024137A1 (en) | 1995-12-28 | 1996-12-13 | HYBRID WITH INTERFERON-α AND AN IMMUNOGLOBULIN Fc LINKED THROUGH A NON-IMMUNOGENIC PEPTIDE |
JP52460997A JP3507507B2 (ja) | 1995-12-28 | 1996-12-13 | 非免疫原性ペプチドを介して結合されたインターフェロン―αと免疫グロブリンとのハイブリッド |
IDP963910A ID16083A (id) | 1995-12-28 | 1996-12-24 | HIBRID DENGAN INTERFERON DAN IMUNOGLOBULIN Fc YANG DIHUBUNGKAN MELALUI PEPTIDA NON-IMUNOGENIK |
TW86110733A TW577896B (en) | 1996-09-25 | 1997-07-28 | Hybrid with interferon-alpha and an immunoglobulin Fc linked through a non-immunogenic peptide |
US08/994,719 US5908626A (en) | 1995-12-28 | 1997-12-19 | Hybrid with interferon-β and an immunoglobulin Fc joined by a peptide linker |
HK99102391A HK1017261A1 (en) | 1995-12-28 | 1999-05-28 | Hybrid with interferon-alpha and an immunoglobulinfc linked through a non-immunogenic peptide. |
US10/917,899 US20050002902A1 (en) | 1995-12-28 | 2004-08-13 | Hybrid with interferon-alpha and an immunoglobulin Fc for treatment of tumors and viral infections |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US57921195A | 1995-12-28 | 1995-12-28 | |
US08/719,331 US5723125A (en) | 1995-12-28 | 1996-09-25 | Hybrid with interferon-alpha and an immunoglobulin Fc linked through a non-immunogenic peptide |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US57921195A Continuation-In-Part | 1995-12-28 | 1995-12-28 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/994,719 Continuation-In-Part US5908626A (en) | 1995-12-28 | 1997-12-19 | Hybrid with interferon-β and an immunoglobulin Fc joined by a peptide linker |
Publications (1)
Publication Number | Publication Date |
---|---|
US5723125A true US5723125A (en) | 1998-03-03 |
Family
ID=27077703
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/719,331 Expired - Fee Related US5723125A (en) | 1995-12-28 | 1996-09-25 | Hybrid with interferon-alpha and an immunoglobulin Fc linked through a non-immunogenic peptide |
US08/994,719 Expired - Fee Related US5908626A (en) | 1995-12-28 | 1997-12-19 | Hybrid with interferon-β and an immunoglobulin Fc joined by a peptide linker |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/994,719 Expired - Fee Related US5908626A (en) | 1995-12-28 | 1997-12-19 | Hybrid with interferon-β and an immunoglobulin Fc joined by a peptide linker |
Country Status (12)
Country | Link |
---|---|
US (2) | US5723125A (de) |
EP (1) | EP0888122B1 (de) |
JP (1) | JP3507507B2 (de) |
CN (1) | CN1187086C (de) |
AT (1) | ATE355074T1 (de) |
AU (1) | AU701579B2 (de) |
CA (1) | CA2239522A1 (de) |
DE (1) | DE69636938T2 (de) |
HK (1) | HK1017261A1 (de) |
ID (1) | ID16083A (de) |
MY (1) | MY116588A (de) |
WO (1) | WO1997024137A1 (de) |
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WO2015053871A2 (en) | 2013-08-26 | 2015-04-16 | MabVax Therapeutics, Inc. | NUCLEIC ACIDS ENCODING HUMAN ANTIBODIES TO SIALYL-LEWISa |
WO2015175375A1 (en) | 2014-05-13 | 2015-11-19 | Short Jay M | Conditionally active biological proteins |
WO2015187811A2 (en) | 2014-06-04 | 2015-12-10 | MabVax Therapeutics, Inc. | Human monoclonal antibodies to ganglioside gd2 |
EP3026123A1 (de) | 2006-04-27 | 2016-06-01 | Klaritos, Inc. | Verfahren und zusammensetzungen zur vorhersage in der antikörper-basierten therapie |
US9381244B2 (en) | 2012-09-07 | 2016-07-05 | King's College London | VISTA modulators for diagnosis and treatment of cancer |
WO2016139482A1 (en) | 2015-03-03 | 2016-09-09 | Kymab Limited | Antibodies, uses & methods |
EP3103880A1 (de) | 2008-02-08 | 2016-12-14 | Ambrx, Inc. | Modifizierte leptinpolypeptide und deren verwendungen |
US9631018B2 (en) | 2010-03-26 | 2017-04-25 | The Trustees Of Dartmouth College | Vista regulatory T cell mediator protein, vista binding agents and use thereof |
US9738702B2 (en) | 2014-03-14 | 2017-08-22 | Janssen Biotech, Inc. | Antibodies with improved half-life in ferrets |
US9890215B2 (en) | 2012-06-22 | 2018-02-13 | King's College London | Vista modulators for diagnosis and treatment of cancer |
WO2018083248A1 (en) | 2016-11-03 | 2018-05-11 | Kymab Limited | Antibodies, combinations comprising antibodies, biomarkers, uses & methods |
WO2019073069A1 (en) | 2017-10-13 | 2019-04-18 | Boehringer Ingelheim International Gmbh | HUMAN ANTIBODIES AGAINST THOMSEN-NEW ANTIGEN (TN) |
US10370455B2 (en) | 2014-12-05 | 2019-08-06 | Immunext, Inc. | Identification of VSIG8 as the putative VISTA receptor (V-R) and use thereof to produce VISTA/VSIG8 agonists and antagonists |
US10428145B2 (en) | 2015-09-29 | 2019-10-01 | Celgene Corporation | PD-1 binding proteins and methods of use thereof |
US10513699B2 (en) | 2014-09-03 | 2019-12-24 | Bioatla, Llc | Discovering and producing conditionally active biologic proteins in the same eukaryotic cell production hosts |
EP3590539A1 (de) | 2014-03-04 | 2020-01-08 | Kymab Limited | Antikörper, verwendungen und verfahren |
WO2020016459A1 (en) | 2018-07-20 | 2020-01-23 | Pierre Fabre Medicament | Receptor for vista |
US10548954B2 (en) | 2010-07-09 | 2020-02-04 | Bioverativ Therapeutics Inc. | Factor IX polypeptides and methods of use thereof |
US10745467B2 (en) | 2010-03-26 | 2020-08-18 | The Trustees Of Dartmouth College | VISTA-Ig for treatment of autoimmune, allergic and inflammatory disorders |
US10751414B2 (en) | 2016-09-19 | 2020-08-25 | Celgene Corporation | Methods of treating psoriasis using PD-1 binding antibodies |
US10766958B2 (en) | 2016-09-19 | 2020-09-08 | Celgene Corporation | Methods of treating vitiligo using PD-1 binding antibodies |
US10766959B2 (en) | 2014-12-11 | 2020-09-08 | Pierre Fabre Medicament | Anti-C10ORF54 antibodies and uses thereof |
EP3738981A1 (de) | 2014-01-24 | 2020-11-18 | NGM Biopharmaceuticals, Inc. | Beta-klotho 2 bindende antikörper und verfahren zur verwendung davon |
US10844122B2 (en) | 2015-05-06 | 2020-11-24 | Janssen Biotech, Inc. | Prostate specific membrane antigen (PSMA) bispecific binding agents and uses thereof |
EP3763740A1 (de) | 2011-01-26 | 2021-01-13 | Celldex Therapeutics, Inc. | Anti-kit-antikörper und verwendungen davon |
US10899836B2 (en) | 2016-02-12 | 2021-01-26 | Janssen Pharmaceutica Nv | Method of identifying anti-VISTA antibodies |
US10933115B2 (en) | 2012-06-22 | 2021-03-02 | The Trustees Of Dartmouth College | VISTA antagonist and methods of use |
US11009509B2 (en) | 2015-06-24 | 2021-05-18 | Janssen Pharmaceutica Nv | Anti-VISTA antibodies and fragments |
US11014987B2 (en) | 2013-12-24 | 2021-05-25 | Janssen Pharmaceutics Nv | Anti-vista antibodies and fragments, uses thereof, and methods of identifying same |
US11041014B2 (en) | 2016-10-28 | 2021-06-22 | S & K Biopharma, Inc. | Lactoferrin/albumin fusion protein and production method therefor |
US11123426B2 (en) | 2014-06-11 | 2021-09-21 | The Trustees Of Dartmouth College | Use of vista agonists and antagonists to suppress or enhance humoral immunity |
US20210292729A1 (en) * | 2010-07-09 | 2021-09-23 | Bioverativ Therapeutics Inc. | Processable single chain molecules and polypeptides made using same |
EP3888690A2 (de) | 2014-05-16 | 2021-10-06 | MedImmune, LLC | Moleküle mit veränderter neonater fc-rezeptorbindung mit verbesserten therapeutischen und diagnostischen eigenschaften |
US11242392B2 (en) | 2013-12-24 | 2022-02-08 | Janssen Pharmaceutica Nv | Anti-vista antibodies and fragments |
WO2022147463A2 (en) | 2020-12-31 | 2022-07-07 | Alamar Biosciences, Inc. | Binder molecules with high affinity and/ or specificity and methods of making and use thereof |
US11472876B2 (en) | 2015-11-02 | 2022-10-18 | Bioatla, Inc. | Conditionally active polypeptides |
US11525000B2 (en) | 2016-04-15 | 2022-12-13 | Immunext, Inc. | Anti-human VISTA antibodies and use thereof |
US11642398B2 (en) | 2013-03-15 | 2023-05-09 | Bioverativ Therapeutics Inc. | Factor IX polypeptide formulations |
WO2023131901A1 (en) | 2022-01-07 | 2023-07-13 | Johnson & Johnson Enterprise Innovation Inc. | Materials and methods of il-1beta binding proteins |
WO2024013727A1 (en) | 2022-07-15 | 2024-01-18 | Janssen Biotech, Inc. | Material and methods for improved bioengineered pairing of antigen-binding variable regions |
WO2024130158A1 (en) | 2022-12-16 | 2024-06-20 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding extended serum half-life interleukin-22 for the treatment of metabolic disease |
Families Citing this family (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030040467A1 (en) | 1998-06-15 | 2003-02-27 | Mary Ann Pelleymounter | Ig/ob fusions and uses thereof. |
US6936439B2 (en) | 1995-11-22 | 2005-08-30 | Amgen Inc. | OB fusion protein compositions and methods |
US20050033033A1 (en) * | 1998-05-04 | 2005-02-10 | Heinz Kohler | Trans-membrane-antibody induced inhibition of apoptosis |
US7569674B2 (en) * | 1998-05-04 | 2009-08-04 | Innexus Biotechnology International Limited | Autophilic antibodies |
US20040185039A1 (en) * | 2002-08-30 | 2004-09-23 | Heinz Kohler | Therapeutic applications of noncovalent dimerizing antibodies |
US20030103984A1 (en) * | 1998-05-04 | 2003-06-05 | Heinz Kohler | Fusion proteins of biologically active peptides and antibodies |
US20090208418A1 (en) * | 2005-04-29 | 2009-08-20 | Innexus Biotechnology Internaltional Ltd. | Superantibody synthesis and use in detection, prevention and treatment of disease |
ATE327254T1 (de) * | 1998-10-16 | 2006-06-15 | Biogen Idec Inc | Interferon-beta fusionsproteine und deren verwendungen |
IL142282A0 (en) * | 1998-10-16 | 2002-03-10 | Biogen Inc | Compositions containing polymer conjugates of interferon-beta-1a |
US6660843B1 (en) * | 1998-10-23 | 2003-12-09 | Amgen Inc. | Modified peptides as therapeutic agents |
EP1250424B1 (de) * | 2000-01-24 | 2007-02-28 | Gendaq, Ltd. | Nucleinsäure bindende polypeptide gekennzeichnet durch flexible linker verbundene nucleinsäuredomäne |
AU2002212107A1 (en) * | 2000-11-02 | 2002-05-15 | Maxygen Aps | New multimeric interferon beta polypeptides |
US20020169290A1 (en) * | 2000-11-02 | 2002-11-14 | Claus Bornaes | New multimeric interferon beta polypeptides |
US7141392B2 (en) * | 2001-01-09 | 2006-11-28 | Queen Mary And Westfield College | Latent fusion protein |
CN1191271C (zh) * | 2001-03-21 | 2005-03-02 | 中国科学院上海生物化学研究所 | 干扰素-胸腺肽融合蛋白及其制法 |
AU2002315157A1 (en) * | 2001-06-14 | 2003-01-02 | Anadys Pharmaceuticals, Inc. | Methods of screening for ligands of target molecules |
US7094757B2 (en) * | 2001-06-22 | 2006-08-22 | Roche Diagnostics Corporation | Complexes comprising a prion protein and a peptidyl prolyl isomerase chaperone, and method for producing and using them |
US6962982B2 (en) * | 2001-06-22 | 2005-11-08 | Roche Diagnostics Corporation | Soluble complexes of target proteins and peptidyl prolyl isomerase chaperones and methods of making and using them |
EP2267452B8 (de) * | 2001-06-22 | 2012-11-14 | Roche Diagnostics GmbH | Löslicher Komplex mit einem retroviralen Oberflächenglykoprotein |
CA2452517A1 (en) * | 2001-07-11 | 2003-01-23 | University Of Miami | Recombinant vsv for the treatment of tumor cells |
US20030104604A1 (en) * | 2001-08-03 | 2003-06-05 | Weiping Yang | Genetically engineered bacterial strains for the display of foreign peptides on filamentous phage |
CN101200503B (zh) * | 2001-08-10 | 2010-07-07 | 中国人民解放军军事医学科学院生物工程研究所 | 血清白蛋白与干扰素的融合蛋白 |
WO2003076567A2 (en) * | 2002-03-05 | 2003-09-18 | Eli Lilly And Company | Heterologous g-csf fusion proteins |
EP1553971A4 (de) * | 2002-07-17 | 2006-07-05 | Biogen Idec Inc | THERAPIEN GEGEN NIERENVERSAGEN MIT INTERFERON-b |
PL376673A1 (pl) * | 2003-02-18 | 2006-01-09 | Merck Patent Gmbh | Białka fuzyjne mutein interferonu alfa o ulepszonych właściwościach |
CN1535724B (zh) * | 2003-04-23 | 2012-09-05 | 北京金迪克生物技术研究所 | 重组人干扰素在制备预防严重性急性呼吸道综合征的药物的用途 |
US20070161087A1 (en) * | 2003-05-29 | 2007-07-12 | Wolfgang Glaesner | Glp-1 fusion proteins |
CN1802386B (zh) * | 2003-06-12 | 2010-12-15 | 伊莱利利公司 | Glp-1类似物融合蛋白质 |
WO2006127757A2 (en) * | 2005-05-26 | 2006-11-30 | Schering Corporation | Interferon-igg fusion |
AU2006286489B2 (en) | 2005-09-01 | 2012-08-09 | Ares Trading S.A. | Treatment of optic neuritis |
US7625564B2 (en) | 2006-01-27 | 2009-12-01 | Novagen Holding Corporation | Recombinant human EPO-Fc fusion proteins with prolonged half-life and enhanced erythropoietic activity in vivo |
JP2009537605A (ja) | 2006-05-24 | 2009-10-29 | メルク セローノ ソシエテ アノニム | 多発性硬化症を治療するためのクラドリビン・レジメン |
BRPI0714334A2 (pt) * | 2006-07-18 | 2013-05-14 | Centocor Inc | mimeticorpos de glp-1 humano aperfeiÇoados, composiÇÕes, mÉtodos e usos |
US20090142362A1 (en) * | 2006-11-06 | 2009-06-04 | Avant Immunotherapeutics, Inc. | Peptide-based vaccine compositions to endogenous cholesteryl ester transfer protein (CETP) |
US7625555B2 (en) | 2007-06-18 | 2009-12-01 | Novagen Holding Corporation | Recombinant human interferon-like proteins |
CA2720628A1 (en) | 2007-07-26 | 2009-01-29 | Novagen Holding Corporation | Fusion proteins having mutated immunoglobulin hinge region |
CN108129573B (zh) | 2007-09-21 | 2021-10-08 | 加利福尼亚大学董事会 | 被导靶的干扰素显示强的细胞凋亡和抗肿瘤活性 |
AU2009274512A1 (en) | 2008-07-25 | 2010-01-28 | The Regents Of The University Of Colorado | Clip inhibitors and methods of modulating immune function |
JP5657698B2 (ja) | 2010-01-19 | 2015-01-21 | ハンミ サイエンス カンパニー リミテッドHanmi Scienceco.,Ltd. | 持続型顆粒球コロニー刺激因子結合体の液剤 |
AR080993A1 (es) | 2010-04-02 | 2012-05-30 | Hanmi Holdings Co Ltd | Formulacion de accion prolongada de interferon beta donde se usa un fragmento de inmunoglobulina |
US20110243943A1 (en) * | 2010-04-02 | 2011-10-06 | Athena Discovery, Inc. | Treatment using relaxin-fusion proteins with extended in vivo half-lives |
EP2558482B1 (de) | 2010-04-16 | 2017-09-27 | Janssen Biotech, Inc. | Genetisch veränderte cysteinproteasen aus pflanzen und ihre verwendung |
CN102585013B (zh) * | 2011-01-07 | 2014-04-23 | 中国人民解放军军事医学科学院生物工程研究所 | 一种含有ω干扰素的融合蛋白及制备方法 |
CN102212139A (zh) * | 2011-03-29 | 2011-10-12 | 中国人民解放军第二军医大学 | 森林脑炎病毒包膜E蛋白与人抗体Fc段融合蛋白及其用途 |
US9243049B2 (en) * | 2011-08-09 | 2016-01-26 | Uab Profarma | Derivatives of recombinant proteins, homo-multimers of granulocyte colony-stimulating factor and method of preparation thereof |
KR102096224B1 (ko) | 2011-10-28 | 2020-04-03 | 테바 파마슈티컬즈 오스트레일리아 피티와이 엘티디 | 폴리펩티드 구축물 및 이의 용도 |
KR20150002588A (ko) * | 2012-01-19 | 2015-01-07 | 에스비씨 버락 바이오테크 코., 엘티디. | 인터페론 및 면역글로불린 fc 섹션 융합 단백질 |
TWI492952B (zh) * | 2012-01-20 | 2015-07-21 | Sbc Virbac Ltd | 動物融合重組型干擾素 |
CN103044554B (zh) * | 2012-05-14 | 2014-08-27 | 旭华(上海)生物研发中心有限公司 | 重组二聚化人尿胰蛋白酶抑制剂、其制备方法及其应用 |
WO2013177231A1 (en) | 2012-05-21 | 2013-11-28 | Massachusetts Institute Of Technology | Translocation of non-natural chemical entities through anthrax protective antigen pore |
US9803021B2 (en) | 2012-12-07 | 2017-10-31 | The Regents Of The University Of California | CD138-targeted interferon demonstrates potent apoptotic and anti-tumor activities |
EP2941243A4 (de) | 2013-01-04 | 2016-09-14 | Massachusetts Inst Technology | Oberflächenbindung bei der verabreichung eines arzneimittels auf nanopartikelbasis in ein gewebe |
DK3677591T5 (da) | 2013-04-29 | 2024-08-26 | Teva Pharmaceuticals Australia Pty Ltd | Anti-CD38 antistoffer og fusioner til svækket interferon alpha-2b |
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WO2014194100A1 (en) | 2013-05-29 | 2014-12-04 | The Regents Of The University Of California | Anti-cspg4 fusions with interferon for the treatment of malignancy |
WO2015161832A1 (zh) * | 2014-04-25 | 2015-10-29 | 辅仁药业集团有限公司 | 长效重组人干扰素α2b-Fc融合蛋白 |
UA119352C2 (uk) | 2014-05-01 | 2019-06-10 | Тева Фармасьютикалз Острейліа Пті Лтд | Комбінація леналідоміду або помалідоміду і конструкції анти-cd38 антитіло-атенуйований інтерферон альфа-2b та спосіб лікування суб'єкта, який має cd38-експресуючу пухлину |
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CN104403004B (zh) | 2014-11-24 | 2017-10-13 | 苏州丁孚靶点生物技术有限公司 | 抗体‑干扰素异二聚体的制备和用途 |
WO2017035508A1 (en) | 2015-08-27 | 2017-03-02 | Collier R John | Compositions and methods for treatment of pain |
TW201718629A (zh) * | 2015-09-25 | 2017-06-01 | 韓美藥品股份有限公司 | 包含多個生理多肽及免疫球蛋白Fc區之蛋白質接合物 |
US20210023236A1 (en) * | 2019-07-26 | 2021-01-28 | Massachusetts Institute Of Technology | Multi-targeted, tunable, sustained delivery of payloads to charged avascular tissues |
EP4047016A1 (de) | 2021-02-19 | 2022-08-24 | Université de Strasbourg | Anti-tenascin-c(tnc)-antikörper (nanobodies) mit einer einzigen domäne und deren verwendung |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0467416A1 (de) * | 1983-09-01 | 1992-01-22 | Hybritech Incorporated | Antikörperzusammensetzungen von therapeutischen Mitteln mit verlängerter Serumhalbwertzeit |
US5349053A (en) * | 1990-06-01 | 1994-09-20 | Protein Design Labs, Inc. | Chimeric ligand/immunoglobulin molecules and their uses |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH648331A5 (de) * | 1979-07-31 | 1985-03-15 | Hoffmann La Roche | Homogenes fibroblasten-interferon und dessen herstellung. |
US4289689A (en) * | 1980-03-14 | 1981-09-15 | Hoffmann-La Roche Inc. | Preparation of homogeneous human fibroblast interferon |
IL58765A (en) * | 1979-11-21 | 1986-09-30 | Yeda Res & Dev | Process for the production of essentially pure messenger rna of human fibroblast interferon and process for the production of interferon beta |
IT1139487B (it) * | 1980-09-25 | 1986-09-24 | Genentech Inc | Produzione microbica di interferone di fibroblasti umani |
JPS57181098A (en) * | 1981-04-30 | 1982-11-08 | Japan Found Cancer | Novel recombinant dna |
JPS58110600A (ja) * | 1981-12-25 | 1983-07-01 | Kyowa Hakko Kogyo Co Ltd | ヒトβ型インタ−フエロン遺伝子を含む組みかえ体プラスミド |
SE436275B (sv) * | 1982-11-01 | 1984-11-26 | Malmbom Rune Ingbyra Hb | Anordning vid en utmed ett underlag rorlig lasthanteringsapparat, foretredesvis en lasttruck |
EP0173494A3 (de) * | 1984-08-27 | 1987-11-25 | The Board Of Trustees Of The Leland Stanford Junior University | Chimäre Rezeptoren durch Verbindung und Expression von DNS |
DE3523701A1 (de) * | 1985-07-03 | 1987-01-08 | Bayer Ag | Verfahren zur herstellung von proteinen und polypeptiden |
DE3712985A1 (de) * | 1987-04-16 | 1988-11-03 | Hoechst Ag | Bifunktionelle proteine |
CA1339445C (en) * | 1986-11-12 | 1997-09-09 | The General Hospital Corporation | Recombinant hybrid immunoglobulin molecules and method of use |
ATE122238T1 (de) * | 1987-06-10 | 1995-05-15 | Dana Farber Cancer Inst Inc | Bifunktionelle antikörperkonstruktionen und verfahren zur selektiven tötung von zellbeständen. |
US4973478A (en) * | 1987-07-20 | 1990-11-27 | Allelix Biopharmaceuticals, Inc. | Treating inflammation with hepatocyte stimulating factor interferon β2 |
SE459586B (sv) * | 1987-09-14 | 1989-07-17 | Mta Szegedi Biolog Koezponti | Strukturgen som kodar foer autentiskt humant serum albumin och foerfarande foer dess framstaellning |
DE3850542T2 (de) * | 1987-09-23 | 1994-11-24 | Bristol Myers Squibb Co | Antikörper-Heterokonjugate zur Töting von HIV-infizierten Zellen. |
NZ226414A (en) * | 1987-10-02 | 1992-07-28 | Genentech Inc | Cd4 peptide adhesion variants and their preparation and use |
GB8725529D0 (en) * | 1987-10-30 | 1987-12-02 | Delta Biotechnology Ltd | Polypeptides |
US4978745A (en) * | 1987-11-23 | 1990-12-18 | Centocor, Inc. | Immunoreactive heterochain antibodies |
US5004605A (en) * | 1987-12-10 | 1991-04-02 | Cetus Corporation | Low pH pharmaceutical compositions of recombinant β-interferon |
PT89484B (pt) * | 1988-01-22 | 1994-03-31 | Gen Hospital Corp | Genes clonados codificadores de proteinas de fusao ig-cd4 e sua utilizacao |
DE68926888T2 (de) * | 1988-01-22 | 1997-01-09 | Zymogenetics Inc | Verfahren zur Herstellung von sekretierten Rezeptoranalogen |
WO1990002338A1 (en) * | 1988-08-19 | 1990-03-08 | The General Hospital Corporation | Recombinant hybrid immunoglobulin molecules and method of use |
CA2010321C (en) * | 1989-02-21 | 2004-04-06 | Thomas F. Tedder | Lymphocyte-associated cell surface protein |
US5225538A (en) * | 1989-02-23 | 1993-07-06 | Genentech, Inc. | Lymphocyte homing receptor/immunoglobulin fusion proteins |
DK0745852T3 (da) * | 1989-03-16 | 2002-10-14 | Blood Res Center | Anvendelse af funktionelle derivater af intercellulær adhæsion-molekylet ICAM-1 i antiviral terapi |
WO1991000360A1 (en) * | 1989-06-29 | 1991-01-10 | Medarex, Inc. | Bispecific reagents for aids therapy |
CA2065010A1 (en) * | 1989-08-23 | 1991-02-24 | Brian Seed | Non-human primate cd4 polypeptides, fusions thereof, dna encoding, and uses thereof |
DK0493418T3 (da) * | 1989-09-20 | 1997-11-03 | Abbott Lab | Fremgangsmåde til fremstilling af fusionsproteiner |
AU7766391A (en) * | 1990-04-23 | 1991-11-11 | Corvas International N.V. | Thrombus-specific antibody derivatives |
-
1996
- 1996-09-25 US US08/719,331 patent/US5723125A/en not_active Expired - Fee Related
- 1996-12-06 MY MYPI96005143A patent/MY116588A/en unknown
- 1996-12-13 CA CA002239522A patent/CA2239522A1/en not_active Abandoned
- 1996-12-13 AU AU13567/97A patent/AU701579B2/en not_active Ceased
- 1996-12-13 DE DE69636938T patent/DE69636938T2/de not_active Expired - Fee Related
- 1996-12-13 CN CNB961994223A patent/CN1187086C/zh not_active Expired - Fee Related
- 1996-12-13 JP JP52460997A patent/JP3507507B2/ja not_active Expired - Fee Related
- 1996-12-13 WO PCT/US1996/020861 patent/WO1997024137A1/en active IP Right Grant
- 1996-12-13 AT AT96945126T patent/ATE355074T1/de not_active IP Right Cessation
- 1996-12-13 EP EP96945126A patent/EP0888122B1/de not_active Expired - Lifetime
- 1996-12-24 ID IDP963910A patent/ID16083A/id unknown
-
1997
- 1997-12-19 US US08/994,719 patent/US5908626A/en not_active Expired - Fee Related
-
1999
- 1999-05-28 HK HK99102391A patent/HK1017261A1/xx not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0467416A1 (de) * | 1983-09-01 | 1992-01-22 | Hybritech Incorporated | Antikörperzusammensetzungen von therapeutischen Mitteln mit verlängerter Serumhalbwertzeit |
US5349053A (en) * | 1990-06-01 | 1994-09-20 | Protein Design Labs, Inc. | Chimeric ligand/immunoglobulin molecules and their uses |
Non-Patent Citations (2)
Title |
---|
Huston, JS et al Methods in Enzymology vol. 203 pp. 46 88, 1991. * |
Huston, JS et al Methods in Enzymology vol. 203 pp. 46-88, 1991. |
Cited By (326)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US7226998B2 (en) | 1997-12-08 | 2007-06-05 | Emd Lexigen Research Center Corp. | Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation |
US7879319B2 (en) | 1997-12-08 | 2011-02-01 | Merk Patent Gmbh | Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation |
US6838260B2 (en) | 1997-12-08 | 2005-01-04 | Emd Lexigen Research Center Corp. | Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation |
US7576193B2 (en) | 1997-12-08 | 2009-08-18 | Merck Patent Gmbh | Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation |
US7026446B1 (en) * | 1997-12-24 | 2006-04-11 | Diatech Pty Ltd. | Bifunctional molecules |
US20060194952A1 (en) * | 1998-02-25 | 2006-08-31 | Emd Lexigen Research Center Corp. | Enhancing the circulating half-life of antibody-based fusion proteins |
US20040180035A1 (en) * | 1998-04-15 | 2004-09-16 | Emd Lexigen Research Center Corp. | IL-15 immunoconjugates and uses thereof |
EP1739090A3 (de) * | 1998-10-16 | 2009-04-08 | Biogen Idec MA Inc. | Interferon Beta Fusions Proteine und deren Gebrauch |
EP1739090A2 (de) * | 1998-10-16 | 2007-01-03 | Biogen Idec MA Inc. | Interferon Beta Fusions Proteine und deren Gebrauch |
US20040076625A1 (en) * | 1998-11-02 | 2004-04-22 | Resistentia Pharmaceuticals Ab, Sweden Corporatin | Enhanced vaccines |
US20050042729A1 (en) * | 1999-05-19 | 2005-02-24 | Emd Lexigen Research Center Corp. | Expression and export of interferon-alpha proteins as Fc fusion proteins |
EP2241623A2 (de) | 1999-07-07 | 2010-10-20 | ZymoGenetics, Inc. | Monoklonaler Antikörper gegen menschlichen Cytokinrezeptor |
AU782496B2 (en) * | 1999-07-13 | 2005-08-04 | Bolder Biotechnology, Inc. | Immunoglobulin fusion proteins |
US7754855B1 (en) | 1999-07-13 | 2010-07-13 | Bolder Biotechnology, Inc. | Immunoglobulin fusion proteins |
US20100285014A1 (en) * | 1999-07-13 | 2010-11-11 | Bolder Biotechnology, Inc. | Immunoglobulin fusion proteins |
WO2001003737A1 (en) * | 1999-07-13 | 2001-01-18 | Bolder Biotechnology Inc. | Immunoglobulin fusion proteins |
US7067110B1 (en) | 1999-07-21 | 2006-06-27 | Emd Lexigen Research Center Corp. | Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens |
US7955590B2 (en) | 1999-07-21 | 2011-06-07 | Merck Patent Gmbh | Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens |
US8043608B2 (en) | 1999-07-21 | 2011-10-25 | Merck Patent Gmbh | Methods of using Fc-cytokine fusion proteins |
US20040072299A1 (en) * | 1999-08-09 | 2004-04-15 | Gillies Stephen D. | Multiple cytokine protein complexes |
US7582288B2 (en) | 1999-08-09 | 2009-09-01 | Merck Patent Gmbh | Methods of targeting multiple cytokines |
US6617135B1 (en) | 1999-08-09 | 2003-09-09 | Emd Lexigen Research Center Corp. | Multiple cytokine protein complexes |
US7141651B2 (en) | 1999-08-09 | 2006-11-28 | Emd Lexigen Research Center Corp. | Multiple cytokine protein complexes |
US20070258944A1 (en) * | 1999-08-09 | 2007-11-08 | Emd Lexigen Research Center Corp. | Multiple cytokine protein complexes |
WO2004022088A1 (en) * | 1999-10-15 | 2004-03-18 | Tanox, Inc. | Interferon and immunoglobulin fc fragment hybrid |
US7211253B1 (en) | 1999-11-12 | 2007-05-01 | Merck Patentgesellschaft Mit Beschrankter Haftung | Erythropoietin forms with improved properties |
US20050202538A1 (en) * | 1999-11-12 | 2005-09-15 | Merck Patent Gmbh | Fc-erythropoietin fusion protein with improved pharmacokinetics |
US7091321B2 (en) * | 2000-02-11 | 2006-08-15 | Emd Lexigen Research Center Corp. | Enhancing the circulating half-life of antibody-based fusion proteins |
US20020147311A1 (en) * | 2000-02-11 | 2002-10-10 | Gillies Stephen D. | Enhancing the circulating half-life of antibody-based fusion proteins |
US7507406B2 (en) | 2000-02-11 | 2009-03-24 | Emd Serono Research Center, Inc. | Enhancing the circulating half-life of antibody-based fusion proteins |
US20060034836A1 (en) * | 2000-02-11 | 2006-02-16 | Emd Lexigen Research Center Corp. | Enhancing the circulating half-life of antibody-based fusion proteins |
US7790415B2 (en) | 2000-02-11 | 2010-09-07 | Merck Patent Gmbh | Enhancing the circulating half-life of antibody-based fusion proteins |
US20100297060A1 (en) * | 2000-06-29 | 2010-11-25 | Merck Patent Gmbh | Enhancement of antibody-cytokine fusion protein mediated immune responses by combined treatment with immunocytokine uptake enhancing agents |
US20030049227A1 (en) * | 2000-06-29 | 2003-03-13 | Gillies Stephen D. | Enhancement of antibody-cytokine fusion protein mediated immune responses by combined treatment with immunocytokine uptake enhancing agents |
US7517526B2 (en) | 2000-06-29 | 2009-04-14 | Merck Patent Gmbh | Enhancement of antibody-cytokine fusion protein mediated immune responses by combined treatment with immunocytokine uptake enhancing agents |
US20130115675A1 (en) * | 2000-12-01 | 2013-05-09 | Verenium Corporation | Dehalogenases, Nucleic Acids Encoding Them and Methods for Making and Using Them |
US9453211B2 (en) * | 2000-12-01 | 2016-09-27 | Basf Enzymes Llc | Dehalogenases, nucleic acids encoding them and methods for making and using them |
EP2341060A1 (de) | 2000-12-12 | 2011-07-06 | MedImmune, LLC | Moleküle mit längeren Halbwertszeiten, Zusammensetzungen und deren Verwendung |
EP2357187A1 (de) | 2000-12-12 | 2011-08-17 | MedImmune, LLC | Moleküle mit längeren Halbwertszeiten, Zusammensetzungen und deren Verwendung |
EP2354149A1 (de) | 2000-12-12 | 2011-08-10 | MedImmune, LLC | Moleküle mit längeren Halbwertszeiten, Zusammensetzungen und deren Verwendung |
EP3569610A2 (de) | 2000-12-12 | 2019-11-20 | Medlmmune, LLC | Moleküle mit verlängerter halbwertzeit, zusammensetzungen und verwendungen dafür |
US7737116B2 (en) | 2001-02-08 | 2010-06-15 | Wyeth | Modified and stabilized GDF propeptides and uses thereof |
US7202210B2 (en) * | 2001-02-08 | 2007-04-10 | Wyeth | Modified and stabilized GDF propeptides and uses thereof |
US8222384B2 (en) | 2001-02-08 | 2012-07-17 | Wyeth Llc | Modified and stabilized GDF propeptides and uses thereof |
US7560441B2 (en) | 2001-02-08 | 2009-07-14 | Wyeth | Modified and stabilized GDF propeptides and uses thereof |
US20070149455A1 (en) * | 2001-02-08 | 2007-06-28 | Wyeth | Modified and stabilized gdf propeptides and uses thereof |
US20100305194A1 (en) * | 2001-02-08 | 2010-12-02 | Wyeth | Modified and stabilized gdf propeptides and uses thereof |
US20030104406A1 (en) * | 2001-02-08 | 2003-06-05 | American Home Products Corporation | Modified and stabilized GDF propeptides and uses thereof |
US20020192682A1 (en) * | 2001-03-01 | 2002-12-19 | Jean-Louis Escary | Polynucleotides and polypeptides of the IFNalpha-2 gene |
US20070025990A1 (en) * | 2001-03-02 | 2007-02-01 | Medimmune, Inc. | Methods of administering/dosing CD2 antagonists for the prevention and treatment of autoimmune disorders or inflammatory disorders |
WO2002070655A2 (en) | 2001-03-02 | 2002-09-12 | Zymogenetics, Inc. | Mouse cytokine receptor |
US20030068320A1 (en) * | 2001-03-02 | 2003-04-10 | Christine Dingivan | Methods of administering/dosing CD2 antagonists for the prevention and treatment of autoimmune disorders or inflammatory disorders |
US20060263856A1 (en) * | 2001-03-07 | 2006-11-23 | Emd Lexigen Research Center Corp. | Expression technology for proteins containing a hybrid isotype antibody moiety |
US8066994B2 (en) | 2001-03-07 | 2011-11-29 | Merck Patent Gmbh | Proteins comprising an IgG2 domain |
US20030044423A1 (en) * | 2001-03-07 | 2003-03-06 | Lexigen Pharmaceuticals Corp. | Expression technology for proteins containing a hybrid isotype antibody moiety |
US7148321B2 (en) | 2001-03-07 | 2006-12-12 | Emd Lexigen Research Center Corp. | Expression technology for proteins containing a hybrid isotype antibody moiety |
US7973150B2 (en) | 2001-03-30 | 2011-07-05 | Merck Patent Gmbh | Reducing the immunogenicity of fusion proteins |
US20060025573A1 (en) * | 2001-03-30 | 2006-02-02 | Merck Patent Gmbh | Reducing the immunogenicity of fusion proteins |
US7601814B2 (en) | 2001-03-30 | 2009-10-13 | Merck Patent Gmbh | Reducing the immunogenicity of fusion proteins |
US8926973B2 (en) | 2001-03-30 | 2015-01-06 | Merck Patent Gmbh | Reducing the immunogenicity of fusion proteins |
US20100016562A1 (en) * | 2001-03-30 | 2010-01-21 | Merck Patent Gmbh | Reducing the immunogenicity of fusion proteins |
US6992174B2 (en) | 2001-03-30 | 2006-01-31 | Emd Lexigen Research Center Corp. | Reducing the immunogenicity of fusion proteins |
US20030166877A1 (en) * | 2001-03-30 | 2003-09-04 | Lexigen Pharmaceuticals Corp. | Reducing the immunogenicity of fusion proteins |
US7041794B2 (en) | 2001-04-04 | 2006-05-09 | Genodyssee | Polynucleotides and polypeptides of the erythropoietin gene |
US20030050269A1 (en) * | 2001-04-04 | 2003-03-13 | Jean-Louis Escary | Polynucleotides and polypeptides of the erythropoietin gene |
US7459538B2 (en) | 2001-05-03 | 2008-12-02 | Merck Patent Gmbh | Recombinant tumor specific antibody and use thereof |
US20030157054A1 (en) * | 2001-05-03 | 2003-08-21 | Lexigen Pharmaceuticals Corp. | Recombinant tumor specific antibody and use thereof |
US20100174056A1 (en) * | 2001-05-03 | 2010-07-08 | Merck Patent Gmbh | Recombinant tumor specific antibody and use thereof |
US7803618B2 (en) | 2001-05-03 | 2010-09-28 | Merck Patent Gmbh | Recombinant tumor specific antibody and use thereof |
US6969517B2 (en) | 2001-05-03 | 2005-11-29 | Emd Lexigen Research Center Corp. | Recombinant tumor specific antibody and use thereof |
US20020193569A1 (en) * | 2001-06-04 | 2002-12-19 | Idec Pharmaceuticals Corporation | Bispecific fusion protein and method of use for enhancing effector cell killing of target cells |
US6900292B2 (en) | 2001-08-17 | 2005-05-31 | Lee-Hwei K. Sun | Fc fusion proteins of human erythropoietin with increased biological activities |
US20030082749A1 (en) * | 2001-08-17 | 2003-05-01 | Sun Lee-Hwei K. | Fc fusion proteins of human erythropoietin with increased biological activities |
US20110020330A1 (en) * | 2001-09-26 | 2011-01-27 | Wyeth | Antibody inhibitors of gdf-8 and uses thereof |
US7731961B1 (en) | 2001-09-26 | 2010-06-08 | Wyeth | Methods of increasing muscle mass or muscle strength using antibody inhibitors of GDF-8 |
US8092798B2 (en) | 2001-09-26 | 2012-01-10 | Wyeth Llc | Method of increasing trabecular bone density in a patient in need thereof by an antibody against GDF-8 |
US9505831B2 (en) | 2001-09-26 | 2016-11-29 | Wyeth Llc | Isolated cell comprising a nucleic acid encoding antibody inhibitors of gdf-8 and uses thereof |
US8710202B2 (en) | 2001-09-26 | 2014-04-29 | Wyeth Llc | Isolated nucleic acid molecule encoding an antibody that reduces GDF-8 activity |
US7320789B2 (en) | 2001-09-26 | 2008-01-22 | Wyeth | Antibody inhibitors of GDF-8 and uses thereof |
US6797493B2 (en) | 2001-10-01 | 2004-09-28 | Lee-Hwei K. Sun | Fc fusion proteins of human granulocyte colony-stimulating factor with increased biological activities |
US7226759B2 (en) | 2001-10-01 | 2007-06-05 | Sun Lee-Hwei K | Fc fusion proteins of human granulocyte colony-stimulating factor with increased biological activities |
US7232668B2 (en) | 2001-10-01 | 2007-06-19 | Sun Lee-Hwei K | Fc fusion proteins of human granulocyte colony-stimulating factor with increased biological activities |
US20040265973A1 (en) * | 2001-10-01 | 2004-12-30 | Sun Lee-Hwei K. | Fc fusion proteins of human granulocyte colony-stimulating factor with increased biological activities |
US20030166163A1 (en) * | 2001-12-04 | 2003-09-04 | Emd Lexigen Research Center Corp. | Immunocytokines with modulated selectivity |
US7462350B2 (en) | 2001-12-04 | 2008-12-09 | Emd Serono Research Center, Inc. | Cancer treatments including administering IL-2 fusion proteins with modulated selectivity |
US20070036752A1 (en) * | 2001-12-04 | 2007-02-15 | Emd Lexigen Research Center Corp. | IL-2 fusion proteins with modulated selectivity |
US7888071B2 (en) | 2001-12-04 | 2011-02-15 | Merck Patent Gmbh | DNA encoding IL-2 fusion proteins with modulated selectivity |
US7186804B2 (en) | 2001-12-04 | 2007-03-06 | Emd Lexigen Research Center Corp. | IL-2 fusion proteins with modulated selectivity |
US20100021462A1 (en) * | 2002-02-21 | 2010-01-28 | Wyeth | Gasp1: a follistatin domain containing protein |
US7192717B2 (en) | 2002-02-21 | 2007-03-20 | Wyeth | GASP1: a follistatin domain containing protein |
US7585835B2 (en) | 2002-02-21 | 2009-09-08 | Wyeth | GASP1: a follistatin domain containing protein |
US20110020372A1 (en) * | 2002-02-21 | 2011-01-27 | Wyeth Llc | Follistatin domain containing proteins |
US7541154B2 (en) | 2002-02-21 | 2009-06-02 | Wyeth | GASP1: a follistatin domain containing protein |
US20030180306A1 (en) * | 2002-02-21 | 2003-09-25 | Wyeth | Follistatin domain containing proteins |
US20070134258A1 (en) * | 2002-02-21 | 2007-06-14 | Wyeth | Gasp1: a follistatin domain containing protein |
US7956038B2 (en) | 2002-02-21 | 2011-06-07 | Wyeth Llc | GASP1: a follistatin domain containing protein |
US20050106154A1 (en) * | 2002-02-21 | 2005-05-19 | Wyeth | GASP1: a follistatin domain containing protein |
US20030162714A1 (en) * | 2002-02-21 | 2003-08-28 | Wyeth | GASP1: a follistatin domain containing protein |
US7572763B2 (en) | 2002-02-21 | 2009-08-11 | Wyeth | Follistatin domain containing proteins |
US20040063912A1 (en) * | 2002-03-15 | 2004-04-01 | The Brigham And Women's Hospital, Inc. | Central airway administration for systemic delivery of therapeutics |
US20040265315A1 (en) * | 2002-09-05 | 2004-12-30 | Christine Dingivan | Methods of preventing or treating T cell malignancies by administering CD2 antagonists |
US20040138118A1 (en) * | 2002-09-16 | 2004-07-15 | Neil Wolfman | Metalloprotease activation of myostatin, and methods of modulating myostatin activity |
EP2298806A1 (de) | 2002-10-16 | 2011-03-23 | Purdue Pharma L.P. | Antikörper, die an zellassoziiertes CA 125/0722P binden, und Verfahren zu deren Anwendung |
EP3301114A1 (de) | 2002-10-16 | 2018-04-04 | Purdue Pharma LP | Fusionspolypeptiden von antikörpern, die an zellassoziiertes ca 125/o722p binden |
EP2891666A1 (de) | 2002-10-16 | 2015-07-08 | Purdue Pharma L.P. | Antikörper, die an zellassoziiertes CA 125/O722P binden, und Verfahren zu deren Anwendung |
US8420082B2 (en) | 2002-10-22 | 2013-04-16 | Wyeth Llc | Neutralizing antibodies against GDF-8 and uses therefor |
US7261893B2 (en) | 2002-10-22 | 2007-08-28 | Wyeth | Neutralizing antibodies against GDF-8 and uses therefor |
US20040142382A1 (en) * | 2002-10-22 | 2004-07-22 | Veldman Geertruida M. | Neutralizing antibodies against GDF-8 and uses therefor |
US8940874B2 (en) | 2002-10-22 | 2015-01-27 | Wyeth Llc | Neutralizing antibodies against GDF-8 and uses therefor |
US20080044410A1 (en) * | 2002-10-22 | 2008-02-21 | Wyeth | Neutralizing antibodies against gdf-8 and uses therefor |
US7655763B2 (en) | 2002-10-22 | 2010-02-02 | Wyeth | Neutralizing antibodies against GDF-8 and uses therefor |
US20040223966A1 (en) * | 2002-10-25 | 2004-11-11 | Wolfman Neil M. | ActRIIB fusion polypeptides and uses therefor |
US20090087375A1 (en) * | 2002-10-25 | 2009-04-02 | Wyeth | ActRIIB Fusion Polypeptides and Uses Therefor |
US20080089897A1 (en) * | 2002-10-25 | 2008-04-17 | Wyeth | ActRIIB Fusion Polypeptides and Uses Therefor |
US7767405B2 (en) | 2002-12-17 | 2010-08-03 | Merck Patent Gmbh | Immunocytokine sequences and uses thereof |
US7169904B2 (en) | 2002-12-17 | 2007-01-30 | Emd Lexigen Research Center Corp. | Immunocytokine sequences and uses thereof |
US20070059282A1 (en) * | 2002-12-17 | 2007-03-15 | Emd Lexigen Research Center Corp. | Immunocytokine sequences and uses thereof |
US20100210831A1 (en) * | 2002-12-17 | 2010-08-19 | Merck Patent Gmbh | Immunocytokine Sequences and Uses Thereof |
US8470991B2 (en) | 2002-12-17 | 2013-06-25 | Merck Patent Gmbh | Immunocytokine sequences and uses thereof |
US20040203100A1 (en) * | 2002-12-17 | 2004-10-14 | Emd Lexigen Research Center Corp. | Immunocytokine sequences and uses thereof |
US20070026014A1 (en) * | 2003-04-17 | 2007-02-01 | Ares Trading S.A. | Interferon beta in severe acute respiratory syndrome (sars) |
US7404956B2 (en) | 2003-05-06 | 2008-07-29 | Syntonix Pharmaceuticals, Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
US20110182896A1 (en) * | 2003-05-06 | 2011-07-28 | Syntonix Pharmaceuticals, Inc. | CLOTTING FACTOR-Fc CHIMERIC PROTEINS TO TREAT HEMOPHILIA |
US20050027109A1 (en) * | 2003-05-06 | 2005-02-03 | Mezo Adam R. | Methods for chemically synthesizing immunoglobulin chimeric proteins |
US8329182B2 (en) | 2003-05-06 | 2012-12-11 | Syntonix Pharmaceuticals, Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
US8449884B2 (en) | 2003-05-06 | 2013-05-28 | Syntonix Pharmaceuticals, Inc. | Clotting factor-fc chimeric proteins to treat hemophilia |
US20050032174A1 (en) * | 2003-05-06 | 2005-02-10 | Peters Robert T. | Immunoglobulin chimeric monomer-dimer hybrids |
US20050037947A1 (en) * | 2003-05-06 | 2005-02-17 | Bitonti Alan J. | Inhibition of drug binding to serum albumin |
US9725496B1 (en) | 2003-05-06 | 2017-08-08 | Bioverative Therapeutics Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
US8815250B2 (en) | 2003-05-06 | 2014-08-26 | Biogen Idec Hemophilia Inc. | Clotting factor-Fc chimeric proteins to treat hemophilia |
US20050147618A1 (en) * | 2003-05-06 | 2005-07-07 | Rivera Daniel S. | Clotting factor-Fc chimeric proteins to treat hemophilia |
US20110182919A1 (en) * | 2003-05-06 | 2011-07-28 | Peters Robert T | Immunoglobulin Chimeric Monomer-Dimer Hybrids |
US9636416B2 (en) | 2003-05-06 | 2017-05-02 | Bioverativ Therapeutics Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
US20050260194A1 (en) * | 2003-05-06 | 2005-11-24 | Peters Robert T | Immunoglobulin chimeric monomer-dimer hybrids |
US8932830B2 (en) | 2003-05-06 | 2015-01-13 | Biogen Idec Hemophilia, Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
US11401322B2 (en) | 2003-05-06 | 2022-08-02 | Bioverativ Therapeutics Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
US7348004B2 (en) | 2003-05-06 | 2008-03-25 | Syntonix Pharmaceuticals, Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
US20080249288A1 (en) * | 2003-05-06 | 2008-10-09 | Syntonix Pharmaceuticals, Inc. | Methods for Chemically Synthesizing Immunoglobulin Chimeric Proteins |
US11168125B2 (en) | 2003-05-06 | 2021-11-09 | Bioverativ Therapeutics Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
US7862820B2 (en) | 2003-05-06 | 2011-01-04 | Syntonix Pharmaceuticals, Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
US20070172928A1 (en) * | 2003-05-06 | 2007-07-26 | Syntonix Pharmaceuticals, Inc. | Immunoglobulin chimeric monomer-dimer hybrids |
US7381408B2 (en) | 2003-05-06 | 2008-06-03 | Syntonix Pharmaceuticals, Inc. | Methods for chemically synthesizing immunoglobulin chimeric proteins |
US7820162B2 (en) | 2003-05-06 | 2010-10-26 | Syntonix Pharmaceuticals, Inc. | Methods for chemically synthesizing immunoglobulin chimeric proteins |
US20100322942A1 (en) * | 2003-06-02 | 2010-12-23 | Wyeth Llc | Therapeutic and prophylactic methods for neuromuscular disorders |
US7785587B2 (en) | 2003-06-02 | 2010-08-31 | Wyeth | Therapeutic methods for muscular or neuromuscular disorders |
US20050069521A1 (en) * | 2003-08-28 | 2005-03-31 | Emd Lexigen Research Center Corp. | Enhancing the circulating half-life of interleukin-2 proteins |
US20070041967A1 (en) * | 2003-11-13 | 2007-02-22 | Jung Sung Y | Igg fc fragment for a drug carrier and method for the preparation thereof |
US7736653B2 (en) | 2003-11-13 | 2010-06-15 | Hanmi Pharm. Co., Ltd | Pharmaceutical composition comprising an immunoglobulin Fc region as a carrier |
US9750820B2 (en) | 2003-11-13 | 2017-09-05 | Hanmi Science Co., Ltd. | IgG Fc fragment for a drug carrier and method for the preparation thereof |
EP2239273A1 (de) | 2003-11-13 | 2010-10-13 | Hanmi Pharmaceutical. Co., Ltd. | Pharmazeutische Zusammensetzung mit einem Immunoglobulin-FC als Träger |
US20100255014A1 (en) * | 2003-11-13 | 2010-10-07 | Hanmi Pharm, Co., Ltd. | Protein Complex Using An Immunoglobulin Fragment and Method For The Preparation Thereof |
US8110665B2 (en) | 2003-11-13 | 2012-02-07 | Hanmi Holdings Co., Ltd. | Pharmaceutical composition comprising an immunoglobulin FC region as a carrier |
WO2005047337A1 (en) | 2003-11-13 | 2005-05-26 | Hanmi Pharmaceutical Co., Ltd. | A pharmaceutical composition comprising an immunoglobulin fc region as a carrier |
US11058776B2 (en) | 2003-11-13 | 2021-07-13 | Hanmi Science Co., Ltd. | IgG Fc fragment for a drug carrier and method for the preparation thereof |
US8822650B2 (en) | 2003-11-13 | 2014-09-02 | Hanmi Science Co., Ltd | Method for the mass production of immunoglobulin constant region |
US7737260B2 (en) | 2003-11-13 | 2010-06-15 | Hanmi Pharm. Co., Ltd | Protein complex using an immunoglobulin fragment and method for the preparation thereof |
US10272159B2 (en) | 2003-11-13 | 2019-04-30 | Hanmi Science Co., Ltd. | IgG Fc fragment for a drug carrier and method for the preparation thereof |
US20060276633A1 (en) * | 2003-11-13 | 2006-12-07 | Jung Sung Y | Method for the mass production of immunoglobulin constant region |
US20060275254A1 (en) * | 2003-11-13 | 2006-12-07 | Hanmi Pharm. Ind. Co., Ltd. | Pharmaceutical composition comprising an immunoglobulin fc region as a carrier |
US20060269553A1 (en) * | 2003-11-13 | 2006-11-30 | Hanmi Pharm. Ind. Co., Ltd. | Protein complex using an immunoglobulin fragment and method for the preparation thereof |
US8029789B2 (en) | 2003-11-13 | 2011-10-04 | Hanmi Holdings Co., Ltd. | Method for the mass production of immunoglobulin constant region |
US10071166B2 (en) | 2003-11-13 | 2018-09-11 | Hanmi Science Co., Ltd. | Protein complex using an immunoglobulin fragment and method for the preparation thereof |
US8846874B2 (en) | 2003-11-13 | 2014-09-30 | Hanmi Science Co., Ltd | IgG Fc fragment for a drug carrier and method for the preparation thereof |
US8338575B2 (en) | 2003-12-30 | 2012-12-25 | Merck Patent Gmbh | IL-7 fusion proteins |
US7323549B2 (en) | 2003-12-30 | 2008-01-29 | Emd Lexigen Research Center Corp. | IL-7 fusion proteins |
US7960514B2 (en) | 2003-12-30 | 2011-06-14 | Merck Patent Gmbh | IL-7 fusion proteins |
US20090010875A1 (en) * | 2003-12-30 | 2009-01-08 | Scott Lauder | IL-7 Fusion Proteins |
US7465447B2 (en) | 2003-12-31 | 2008-12-16 | Merck Patent Gmbh | Fc-erythropoietin fusion protein with improved pharmacokinetics |
US20050192211A1 (en) * | 2003-12-31 | 2005-09-01 | Emd Lexigen Research Center Corp. | Fc-erythropoietin fusion protein with improved pharmacokinetics |
US20090092607A1 (en) * | 2003-12-31 | 2009-04-09 | Merck Patent Gmbh | Fc-erythropoietin fusion protein with improved pharmacokinetics |
US7432357B2 (en) | 2004-01-22 | 2008-10-07 | Merck Patent Gmbh | Anti-cancer antibodies with reduced complement fixation |
US20050202021A1 (en) * | 2004-01-22 | 2005-09-15 | Emd Lexigen Research Center Corp. | Anti-cancer antibodies with reduced complement fixation |
US20090148441A1 (en) * | 2004-01-22 | 2009-06-11 | Merck Patent Gmbh | Anti-Cancer Antibodies With Reduced Complement Fixation |
US8835606B2 (en) | 2004-01-22 | 2014-09-16 | Merck Patent Gmbh | Anti-cancer antibodies with reduced complement fixation |
US10017579B2 (en) | 2004-01-22 | 2018-07-10 | Meck Patent Gmbh | Anti-cancer antibodies with reduced complement fixation |
US10633452B2 (en) | 2004-01-22 | 2020-04-28 | Merck Patent Gmbh | Anti-cancer antibodies with reduced complement fixation |
US9617349B2 (en) | 2004-01-22 | 2017-04-11 | Merck Patent Gmbh | Anti-cancer antibodies with reduced complement fixation |
US8097702B2 (en) | 2004-02-02 | 2012-01-17 | Ambrx, Inc. | Modified human interferon polypeptides with at least one non-naturally encoded amino acid and their uses |
US20050220762A1 (en) * | 2004-02-02 | 2005-10-06 | Ambrx, Inc. | Modified human interferon polypeptides and their uses |
US8119603B2 (en) | 2004-02-02 | 2012-02-21 | Ambrx, Inc. | Modified human interferon polypeptides and their uses |
US8232371B2 (en) | 2004-02-02 | 2012-07-31 | Ambrx, Inc. | Modified human interferon polypeptides and their uses |
US20060228332A1 (en) * | 2004-06-28 | 2006-10-12 | Merck Patent Gmbh | Assembly and folding of Fc-interferon-beta fusion proteins |
US8557232B2 (en) | 2004-06-28 | 2013-10-15 | Merck Patent Gmbh | Stabilization of Fc-interferon-beta fusion proteins |
US7670595B2 (en) | 2004-06-28 | 2010-03-02 | Merck Patent Gmbh | Fc-interferon-beta fusion proteins |
US20090191154A1 (en) * | 2004-06-28 | 2009-07-30 | Merck Patent Gmbh | Assembly and folding of fc-interferon-beta fusion proteins |
US20060034831A1 (en) * | 2004-08-12 | 2006-02-16 | Wyeth | Combination therapy for diabetes, obesity and cardiovascular diseases using GDF-8 inhibitors |
US20090249503A1 (en) * | 2004-12-06 | 2009-10-01 | Bolder Biotechnology, Inc. | Enzyme conjugates for use as detoxifying agents |
US20060141581A1 (en) * | 2004-12-09 | 2006-06-29 | Merck Patent Gmbh | IL-7 variants with reduced immunogenicity |
US7589179B2 (en) | 2004-12-09 | 2009-09-15 | Merck Patent Gmbh | IL-7 variants with reduced immunogenicity |
EP2192132A2 (de) | 2005-02-08 | 2010-06-02 | ZymoGenetics, Inc. | Anti-il-20-, Anti-il-22- und Anti-il-22ra-Antikörper und Bindungspartner sowie Verwendungsverfahren bei Entzündungen |
US20060240488A1 (en) * | 2005-03-23 | 2006-10-26 | Nowak John A | Detection of an immune response to GDF-8 modulating agents |
WO2006107124A1 (en) | 2005-04-08 | 2006-10-12 | Hanmi Pharmaceutical Co., Ltd. | Immunoglobulin fc fragment modified by non-peptide polymer and pharmaceutical composition comprising the same |
EP3214095A1 (de) | 2005-05-12 | 2017-09-06 | ZymoGenetics, Inc. | Zusammensetzungen und verfahren zur modulation von immunsystemreaktionen |
EP3683230A1 (de) | 2005-05-12 | 2020-07-22 | ZymoGenetics, Inc. | Zusammensetzungen und verfahren zur modulation von immunsystemreaktionen |
EP2397493A1 (de) | 2005-05-12 | 2011-12-21 | ZymoGenetics, Inc. | Zusammensetzungen und Verfahren zur Modulation von Immunantworten |
EP2399932A1 (de) | 2005-05-12 | 2011-12-28 | ZymoGenetics, Inc. | Zusammensetzungen und Verfahren zur Modulation von Immunantworten |
US20080293106A1 (en) * | 2005-08-16 | 2008-11-27 | Jung Sung Youb | Method For the Mass Production of Immunoglobulin Fc Region Deleted Initial Methionine Residues |
US7968316B2 (en) | 2005-08-16 | 2011-06-28 | Hanmi Holdings Co., Ltd. | Method for the mass production of immunoglobulin Fc region deleted initial methionine residues |
WO2007021129A1 (en) | 2005-08-16 | 2007-02-22 | Hanmi Pharmaceutical Co., Ltd. | A method for the mass production of immunoglobulin fc region deleted initial methionine residues |
US20070104689A1 (en) * | 2005-09-27 | 2007-05-10 | Merck Patent Gmbh | Compositions and methods for treating tumors presenting survivin antigens |
US20110097792A1 (en) * | 2005-12-30 | 2011-04-28 | Merck Patent Gmbh | Interleukin-12p40 variants with improved stability |
US20070154453A1 (en) * | 2005-12-30 | 2007-07-05 | Merck Patent Gmbh | Interleukin-12p40 variants with improved stability |
US7872107B2 (en) | 2005-12-30 | 2011-01-18 | Merck Patent Gmbh | Interleukin-12p40 variants with improved stability |
US8691952B2 (en) | 2005-12-30 | 2014-04-08 | Merck Patent Gmbh | Anti-CD19 antibodies with reduced immunogenicity |
US10072092B2 (en) | 2005-12-30 | 2018-09-11 | Merck Patent Gmbh | Methods of use of anti-CD19 antibodies with reduced immunogenicity |
US9029330B2 (en) | 2005-12-30 | 2015-05-12 | Merck Patent Gmbh | Methods of treating cancer using interleukin-12p40 variants having improved stability |
US20070154473A1 (en) * | 2005-12-30 | 2007-07-05 | Merck Patent Gmbh | Anti-CD19 antibodies with reduced immunogenicity |
US8188248B2 (en) | 2005-12-30 | 2012-05-29 | Merck Patent Gmbh | Nucleic acids encoding interleukin-12P40 variants with improved stability |
US8957195B2 (en) | 2005-12-30 | 2015-02-17 | Merck Patent Gmbh | Anti-CD19 antibodies with reduced immunogenicity |
US11208496B2 (en) | 2005-12-30 | 2021-12-28 | Cancer Research Technology Ltd. | Anti-CD19 antibodies with reduced immunogenicity |
EP3026123A1 (de) | 2006-04-27 | 2016-06-01 | Klaritos, Inc. | Verfahren und zusammensetzungen zur vorhersage in der antikörper-basierten therapie |
EP2484696A1 (de) | 2006-08-28 | 2012-08-08 | Kyowa Hakko Kirin Co., Ltd. | Antagonistische hLIGHT-spezifische menschliche monoklonale Antikörper |
EP2292663A2 (de) | 2006-08-28 | 2011-03-09 | Kyowa Hakko Kirin Co., Ltd. | Antagonistische humane monoklonale Antikörper spezifisch für humanes LIGHT |
EP2407548A1 (de) | 2006-10-16 | 2012-01-18 | MedImmune, LLC | Moleküle mit reduzierter Halbwertzeit, Zusammensetzungen und ihre Verwendung |
WO2008075833A1 (en) | 2006-12-21 | 2008-06-26 | Mogam Biotechnology Research Institute | Fusion protein of immunoglobulin fc and human apolipoprotein(a) kringle fragment |
US20100196370A1 (en) * | 2006-12-21 | 2010-08-05 | Mogam Biotechnology Research Institute | Fusion protein of immunoglobulin fc and human apolipoprotein(a) kringle fragment |
EP2703007A1 (de) | 2007-03-30 | 2014-03-05 | MedImmune, LLC | Antikörper mit verminderten Deamidierungsprofilen |
WO2009046407A2 (en) | 2007-10-04 | 2009-04-09 | Zymogenetics, Inc. | B7 FAMILY MEMBER zB7H6 AND RELATED COMPOSITIONS AND METHODS |
EP3241846A1 (de) | 2007-10-04 | 2017-11-08 | ZymoGenetics, Inc. | B7-familienmitglied zb7h6 sowie zugehörige zusammensetzungen und verfahren |
EP2952524A1 (de) | 2007-10-17 | 2015-12-09 | Janssen Sciences Ireland UC | Vom apoe-status abhängige immuntherapiedosierungen |
WO2009052439A2 (en) | 2007-10-17 | 2009-04-23 | Elan Pharma International Limited | Immunotherapy regimes dependent on apoe status |
EP2602263A2 (de) | 2007-11-21 | 2013-06-12 | Roskilde Universitet | Polypeptide mit ice-bindender Aktivität |
US20110027337A1 (en) * | 2007-12-21 | 2011-02-03 | Ifxa A/S | Protease inhibitor |
US20100310646A1 (en) * | 2008-01-25 | 2010-12-09 | Claus Oxvig | Selective exosite inhibition of papp-a activity against igfbp-4 |
US8653020B2 (en) | 2008-01-25 | 2014-02-18 | Aarhus Universitet | Selective exosite inhibition of PAPP-A activity against IGFBP-4 |
EP3103880A1 (de) | 2008-02-08 | 2016-12-14 | Ambrx, Inc. | Modifizierte leptinpolypeptide und deren verwendungen |
WO2010011096A2 (en) | 2008-07-23 | 2010-01-28 | Hanmi Pharmaceutical Co., Ltd. | A polypeptide complex comprising non-peptidyl polymer having three functional ends |
US8907066B2 (en) | 2009-04-22 | 2014-12-09 | Merck Patent Gmbh | Antibody fusion proteins with a modified FcRn binding site |
US20100272720A1 (en) * | 2009-04-22 | 2010-10-28 | Merck Patent Gmbh | Antibody Fusion Proteins with a Modified FcRn Binding Site |
WO2010141329A1 (en) | 2009-06-01 | 2010-12-09 | Medimmune, Llc | Molecules with extended half-lives and uses thereof |
WO2011020079A1 (en) | 2009-08-13 | 2011-02-17 | Calmune Corporation | Antibodies against human respiratory syncytial virus (rsv) and methods of use |
US9403900B2 (en) | 2009-08-13 | 2016-08-02 | Crucell Holland B.V. | Anti-human respiratory syncytial virus (RSV) antibodies and methods of use |
US8568719B2 (en) | 2009-08-13 | 2013-10-29 | Crucell Holland B.V. | Antibodies against human respiratory syncytial virus (RSV) and methods of use |
WO2011020024A2 (en) | 2009-08-13 | 2011-02-17 | The Johns Hopkins University | Methods of modulating immune function |
US9988437B2 (en) | 2009-08-13 | 2018-06-05 | Janssen Vaccines & Prevention B.V. | Anti-human Respiratory Syncytial Virus (RSV) antibodies and methods of use |
US9365638B2 (en) | 2009-08-13 | 2016-06-14 | Crucell Holland B. V. | Antibodies against human respiratory syncytial virus (RSV) and methods of use |
EP3381937A2 (de) | 2009-08-13 | 2018-10-03 | The Johns Hopkins University | Verfahren zur modulierung der immunfunktion |
US20110076268A1 (en) * | 2009-08-13 | 2011-03-31 | Robert Anthony Williamson | Antibodies against human respiratory syncytial virus (RSV) and methods of use |
WO2011035205A2 (en) | 2009-09-18 | 2011-03-24 | Calmune Corporation | Antibodies against candida, collections thereof and methods of use |
US12071473B2 (en) | 2010-03-26 | 2024-08-27 | The Trustees Of Darmouth College | VISTA-Ig for treatment of autoimmune, allergic and inflammatory disorders |
US10745467B2 (en) | 2010-03-26 | 2020-08-18 | The Trustees Of Dartmouth College | VISTA-Ig for treatment of autoimmune, allergic and inflammatory disorders |
US9631018B2 (en) | 2010-03-26 | 2017-04-25 | The Trustees Of Dartmouth College | Vista regulatory T cell mediator protein, vista binding agents and use thereof |
US10781254B2 (en) | 2010-03-26 | 2020-09-22 | The Trustees Of Dartmouth College | VISTA regulatory T cell mediator protein, VISTA binding agents and use thereof |
US10548954B2 (en) | 2010-07-09 | 2020-02-04 | Bioverativ Therapeutics Inc. | Factor IX polypeptides and methods of use thereof |
US20210292729A1 (en) * | 2010-07-09 | 2021-09-23 | Bioverativ Therapeutics Inc. | Processable single chain molecules and polypeptides made using same |
WO2012006596A2 (en) | 2010-07-09 | 2012-01-12 | Calmune Corporation | Anti-human respiratory syncytial virus (rsv) antibodies and methods of use |
US9139642B2 (en) | 2010-07-09 | 2015-09-22 | Crucell Holland B.V. | Anti-human respiratory syncytial virus (RSV) antibodies and methods of use |
US10561714B2 (en) | 2010-07-09 | 2020-02-18 | Bioverativ Therapeutics Inc. | Factor IX polypeptides and methods of use thereof |
US10898554B1 (en) | 2010-07-09 | 2021-01-26 | Bioverativ Therapeutics Inc. | Factor IX polypeptides and methods of use thereof |
US10568943B2 (en) | 2010-07-09 | 2020-02-25 | Bioverativ Therapeutics Inc. | Factor IX polypeptides and methods of use thereof |
EP3763740A1 (de) | 2011-01-26 | 2021-01-13 | Celldex Therapeutics, Inc. | Anti-kit-antikörper und verwendungen davon |
WO2013052456A1 (en) | 2011-10-05 | 2013-04-11 | Nanosys, Inc. | Silicon nanostructure active materials for lithium ion batteries and processes, compositions, components, and devices related thereto |
EP3252075A1 (de) | 2011-11-04 | 2017-12-06 | Novartis AG | Halbwertszeitverlängererkonstrukte aus low-density-lipoprotein-verwandtem protein 6 (lrp6) |
EP3290442A1 (de) | 2011-11-04 | 2018-03-07 | Novartis AG | Halbwertszeitverlängererkonstrukte aus low-density-lipoprotein-verwandtem protein 6 (lrp6) |
WO2013067355A1 (en) | 2011-11-04 | 2013-05-10 | Novartis Ag | Low density lipoprotein-related protein 6 (lrp6) - half life extender constructs |
KR20150008870A (ko) | 2012-04-23 | 2015-01-23 | 가부시키가이샤 엔알엘 파마 | 락토페린 융합 단백질 및 그의 제조방법 |
US9809641B2 (en) | 2012-04-23 | 2017-11-07 | Nrl Pharma, Inc. | Lactoferrin fusion protein and method for preparation thereof |
WO2013162050A1 (ja) | 2012-04-23 | 2013-10-31 | 株式会社Nrlファーマ | ラクトフェリン融合タンパク質及びその製造方法 |
US10562959B2 (en) | 2012-04-23 | 2020-02-18 | Nrl Pharma, Inc. | Lactoferrin fusion protein and method for preparation thereof |
US11180557B2 (en) | 2012-06-22 | 2021-11-23 | King's College London | Vista modulators for diagnosis and treatment of cancer |
AU2013277051B2 (en) * | 2012-06-22 | 2018-06-07 | King's College London | Novel VISTA-Ig constructs and the use of VISTA-Ig for treatment of autoimmune, allergic and inflammatory disorders |
US12064463B2 (en) | 2012-06-22 | 2024-08-20 | King's College London | Vista antagonist and methods of use |
US9890215B2 (en) | 2012-06-22 | 2018-02-13 | King's College London | Vista modulators for diagnosis and treatment of cancer |
EP3421486A1 (de) * | 2012-06-22 | 2019-01-02 | The Trustees Of Dartmouth College | Neuartige vista-ig-konstrukte und verwendung von vista-ig zur behandlung von autoimmun-, allergischen und entzündungserkrankungen |
US11752189B2 (en) | 2012-06-22 | 2023-09-12 | The Trustees Of Dartmouth College | Vista antagonist and methods of use |
US10933115B2 (en) | 2012-06-22 | 2021-03-02 | The Trustees Of Dartmouth College | VISTA antagonist and methods of use |
WO2013192504A1 (en) * | 2012-06-22 | 2013-12-27 | The Trustees Of Dartmouth College | Novel vista-ig constructs and the use of vista-ig for treatment of autoimmune, allergic and inflammatory disorders |
WO2014018625A1 (en) | 2012-07-25 | 2014-01-30 | Kolltan Pharmaceuticals, Inc. | Anti-kit antibodies and uses thereof |
EP3381943A1 (de) | 2012-07-25 | 2018-10-03 | Celldex Therapeutics, Inc. | Anti-kit-antikörper und verwendungen davon |
EP4063391A1 (de) | 2012-07-25 | 2022-09-28 | Celldex Therapeutics, Inc. | Anti-kit-antikörper und verwendungen davon |
US11529416B2 (en) | 2012-09-07 | 2022-12-20 | Kings College London | Vista modulators for diagnosis and treatment of cancer |
US9381244B2 (en) | 2012-09-07 | 2016-07-05 | King's College London | VISTA modulators for diagnosis and treatment of cancer |
WO2014059028A1 (en) | 2012-10-09 | 2014-04-17 | Igenica, Inc. | Anti-c16orf54 antibodies and methods of use thereof |
US11642398B2 (en) | 2013-03-15 | 2023-05-09 | Bioverativ Therapeutics Inc. | Factor IX polypeptide formulations |
US10421818B2 (en) | 2013-06-06 | 2019-09-24 | Pierre Fabre Medicament | Anti-C10orf54 antibodies and uses thereof |
US10100123B2 (en) | 2013-06-06 | 2018-10-16 | Pierre Fabre Medicament | Anti-C10orf54 antibodies and uses thereof |
WO2014197849A2 (en) | 2013-06-06 | 2014-12-11 | Igenica Biotherapeutics, Inc. | Anti-c10orf54 antibodies and uses thereof |
US10414823B2 (en) | 2013-06-06 | 2019-09-17 | Pierre Fabre Medicament | Anti-C10orf54 antibodies and uses thereof |
WO2014202089A2 (en) | 2013-06-18 | 2014-12-24 | Roskilde Universitet | Variants of anti-freeze polypeptides |
WO2015005748A1 (ko) | 2013-07-12 | 2015-01-15 | 한미약품 주식회사 | 수용체-매개 제거가 감소된, 생리활성 폴리펩타이드 단량체-면역글로불린 Fc 단편 결합체 및 이의 제조방법 |
US10487128B2 (en) | 2013-07-12 | 2019-11-26 | Hanmi Pharm. Co., Ltd | Conjugate of biologically active polypeptide monomer and immunoglobulin Fc fragment with reduced receptor-mediated clearance, and the method for preparing the same |
EP3906945A2 (de) | 2013-08-26 | 2021-11-10 | BioNTech Research and Development, Inc. | Nukleinsäuren, die menschliche antikörper gegen sialyl-lewis a codieren |
WO2015053871A2 (en) | 2013-08-26 | 2015-04-16 | MabVax Therapeutics, Inc. | NUCLEIC ACIDS ENCODING HUMAN ANTIBODIES TO SIALYL-LEWISa |
US9475874B2 (en) | 2013-08-26 | 2016-10-25 | MabVax Therapeutics, Inc. | Nucleic acids encoding human antibodies to sialyl-lewisa |
US11242392B2 (en) | 2013-12-24 | 2022-02-08 | Janssen Pharmaceutica Nv | Anti-vista antibodies and fragments |
US11014987B2 (en) | 2013-12-24 | 2021-05-25 | Janssen Pharmaceutics Nv | Anti-vista antibodies and fragments, uses thereof, and methods of identifying same |
EP3738981A1 (de) | 2014-01-24 | 2020-11-18 | NGM Biopharmaceuticals, Inc. | Beta-klotho 2 bindende antikörper und verfahren zur verwendung davon |
EP3590539A1 (de) | 2014-03-04 | 2020-01-08 | Kymab Limited | Antikörper, verwendungen und verfahren |
US9738702B2 (en) | 2014-03-14 | 2017-08-22 | Janssen Biotech, Inc. | Antibodies with improved half-life in ferrets |
WO2015175375A1 (en) | 2014-05-13 | 2015-11-19 | Short Jay M | Conditionally active biological proteins |
US10329556B2 (en) | 2014-05-13 | 2019-06-25 | Bioatla, Llc | Conditionally active biological proteins |
EP3888690A2 (de) | 2014-05-16 | 2021-10-06 | MedImmune, LLC | Moleküle mit veränderter neonater fc-rezeptorbindung mit verbesserten therapeutischen und diagnostischen eigenschaften |
WO2015187811A2 (en) | 2014-06-04 | 2015-12-10 | MabVax Therapeutics, Inc. | Human monoclonal antibodies to ganglioside gd2 |
US11760809B2 (en) | 2014-06-04 | 2023-09-19 | BioNTech SE | Human monoclonal antibodies to ganglioside GD2 |
US9856324B2 (en) | 2014-06-04 | 2018-01-02 | MabVax Therapeutics, Inc. | Human monoclonal antibodies to ganglioside GD2 |
EP3868405A1 (de) | 2014-06-04 | 2021-08-25 | BioNTech Research and Development, Inc. | Humane monoklonale antikörper gegen gangliosid gd2 |
US10906988B2 (en) | 2014-06-04 | 2021-02-02 | Biontech Research And Development, Inc. | Human monoclonal antibodies to ganglioside GD2 |
US11123426B2 (en) | 2014-06-11 | 2021-09-21 | The Trustees Of Dartmouth College | Use of vista agonists and antagonists to suppress or enhance humoral immunity |
US10513699B2 (en) | 2014-09-03 | 2019-12-24 | Bioatla, Llc | Discovering and producing conditionally active biologic proteins in the same eukaryotic cell production hosts |
US10370455B2 (en) | 2014-12-05 | 2019-08-06 | Immunext, Inc. | Identification of VSIG8 as the putative VISTA receptor (V-R) and use thereof to produce VISTA/VSIG8 agonists and antagonists |
US10766959B2 (en) | 2014-12-11 | 2020-09-08 | Pierre Fabre Medicament | Anti-C10ORF54 antibodies and uses thereof |
EP3800202A1 (de) | 2014-12-11 | 2021-04-07 | Pierre Fabre Medicament | Anti-c10orf54-antikörper und verwendungen davon |
US11873339B2 (en) | 2014-12-11 | 2024-01-16 | Pierre Fabre Medicament | Anti-C10orf54 antibodies and uses thereof |
EP4137157A1 (de) | 2015-03-03 | 2023-02-22 | Kymab Limited | Antikörper, verwendungen und verfahren |
WO2016139482A1 (en) | 2015-03-03 | 2016-09-09 | Kymab Limited | Antibodies, uses & methods |
US10844122B2 (en) | 2015-05-06 | 2020-11-24 | Janssen Biotech, Inc. | Prostate specific membrane antigen (PSMA) bispecific binding agents and uses thereof |
US11009509B2 (en) | 2015-06-24 | 2021-05-18 | Janssen Pharmaceutica Nv | Anti-VISTA antibodies and fragments |
US10428145B2 (en) | 2015-09-29 | 2019-10-01 | Celgene Corporation | PD-1 binding proteins and methods of use thereof |
US11472876B2 (en) | 2015-11-02 | 2022-10-18 | Bioatla, Inc. | Conditionally active polypeptides |
US11987630B2 (en) | 2016-02-12 | 2024-05-21 | Janssen Pharmaceutica Nv | Anti-vista antibodies and fragments, uses thereof, and methods of identifying same |
US10899836B2 (en) | 2016-02-12 | 2021-01-26 | Janssen Pharmaceutica Nv | Method of identifying anti-VISTA antibodies |
US11603403B2 (en) | 2016-04-15 | 2023-03-14 | Immunext, Inc. | Anti-human vista antibodies and use thereof |
US11525000B2 (en) | 2016-04-15 | 2022-12-13 | Immunext, Inc. | Anti-human VISTA antibodies and use thereof |
US11603402B2 (en) | 2016-04-15 | 2023-03-14 | Immunext, Inc. | Anti-human vista antibodies and use thereof |
US11649283B2 (en) | 2016-04-15 | 2023-05-16 | Immunext, Inc. | Anti-human vista antibodies and use thereof |
US10751414B2 (en) | 2016-09-19 | 2020-08-25 | Celgene Corporation | Methods of treating psoriasis using PD-1 binding antibodies |
US10766958B2 (en) | 2016-09-19 | 2020-09-08 | Celgene Corporation | Methods of treating vitiligo using PD-1 binding antibodies |
US11041014B2 (en) | 2016-10-28 | 2021-06-22 | S & K Biopharma, Inc. | Lactoferrin/albumin fusion protein and production method therefor |
WO2018083248A1 (en) | 2016-11-03 | 2018-05-11 | Kymab Limited | Antibodies, combinations comprising antibodies, biomarkers, uses & methods |
WO2019073069A1 (en) | 2017-10-13 | 2019-04-18 | Boehringer Ingelheim International Gmbh | HUMAN ANTIBODIES AGAINST THOMSEN-NEW ANTIGEN (TN) |
WO2020016459A1 (en) | 2018-07-20 | 2020-01-23 | Pierre Fabre Medicament | Receptor for vista |
WO2022147463A2 (en) | 2020-12-31 | 2022-07-07 | Alamar Biosciences, Inc. | Binder molecules with high affinity and/ or specificity and methods of making and use thereof |
WO2023131901A1 (en) | 2022-01-07 | 2023-07-13 | Johnson & Johnson Enterprise Innovation Inc. | Materials and methods of il-1beta binding proteins |
WO2024013727A1 (en) | 2022-07-15 | 2024-01-18 | Janssen Biotech, Inc. | Material and methods for improved bioengineered pairing of antigen-binding variable regions |
WO2024130158A1 (en) | 2022-12-16 | 2024-06-20 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding extended serum half-life interleukin-22 for the treatment of metabolic disease |
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ATE355074T1 (de) | 2006-03-15 |
DE69636938D1 (de) | 2007-04-12 |
MY116588A (en) | 2004-02-28 |
EP0888122A4 (de) | 2002-01-09 |
DE69636938T2 (de) | 2007-11-08 |
EP0888122B1 (de) | 2007-02-28 |
AU1356797A (en) | 1997-07-28 |
JPH11505132A (ja) | 1999-05-18 |
CA2239522A1 (en) | 1997-07-10 |
AU701579B2 (en) | 1999-02-04 |
CN1206350A (zh) | 1999-01-27 |
WO1997024137A1 (en) | 1997-07-10 |
JP3507507B2 (ja) | 2004-03-15 |
CN1187086C (zh) | 2005-02-02 |
EP0888122A1 (de) | 1999-01-07 |
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ID16083A (id) | 1997-09-04 |
US5908626A (en) | 1999-06-01 |
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